Targeted-pig trial on safety and immunogenicity of serum-derived extracellular vesicles enriched fractions obtained from Porcine Respiratory and Reproductive virus infections

The Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is the etiological agent of one of the most important swine diseases with a significant economic burden worldwide. Unfortunately, available vaccines are partially effective highlighting the need of novel approaches. Previously, antigenic viral proteins were described in serum-derived extracellular vesicles (EVs) from pigs previously infected with PRRSV. Here, a targeted-pig trial was designed to determine the safety and immunogenicity of such extracellular vesicles enriched fractions. Our results showed that immunizations with EV-enriched fractions from convalescence animals in combination with montanide is safe and free of virus as immunizations with up-to two milligrams of EV-enriched fractions did not induce clinical symptoms, adverse effects and detectable viral replication. In addition, this vaccine formulation was able to elicit specific humoral IgG immune response in vaccinated animals, albeit variably. Noticeably, sera from vaccinated animals was diagnosed negative when tested for PRRSV using a commercial ELISA test; thus, indicating that this new approach differentiates vaccinated from infected animals. Lastly, after priming animals with EV-enriched fractions from sera of convalescence animals and boosting them with synthetic viral peptides identified by mass spectrometry, a distinctive high and specific IFN-γ response was elicited. Altogether, our data strongly suggest the use of serum EV-enriched fractions as a novel vaccine strategy against PRRSV.Anti-CD9, Anti-CD63 and anti-CD81 antibodies were kindly donated by Francisco Sánchez-Madrid and Maria Yañez-Mo, Hospital de la Princesa, Madrid, Spain. The authors wish to particularly thank Glòria Abella for her collaboration in conducting the field study and to Marta Alcobé, Miriam Moron Font and Paula Crego Mendez for technical assistance. This study received support from Innovex Therapeutics S.L., Pinsos del Segre SA, Granja Casanyé, Grup de Sanejament Porci (GSP, Lleida, Spain) and the FEDER project (COMRDI16-1-0035-03). Sergio Montanter-Tarbes is an industrial doctorate awarded by the Government of Catalonia, Spain (No. 2014 DI 044). ISGlobal and IGTP are members of the CERCA Programme, Generalitat de Catalunya

Efficient finite element methodology based on cartesian grids: application to structural shape optimization

This work presents an analysis methodology based on the use of the Finite Element Method (FEM) nowadays considered one of the main numerical tools for solving Boundary Value Problems (BVPs). The proposed methodology, so-called cg-FEM (Cartesian grid FEM), has been implemented for fast and accurate numerical analysis of 2D linear elasticity problems. The traditional FEM uses geometry-conforming meshes; however, in cg-FEM the analysis mesh is not conformal to the geometry. This allows for defining very efficient mesh generation techniques and using a robust integration procedure, to accurately integrate the domain's geometry. The hierarchical data structure used in cg-FEM together with the Cartesian meshes allow for trivial data sharing between similar entities. The cg-FEM methodology uses advanced recovery techniques to obtain an improved solution of the displacement and stress fields (for which a discretization error estimator in energy norm is available) that will be the output of the analysis. All this results in a substantial increase in accuracy and computational efficiency with respect to the standard FEM. cg-FEM has been applied in structural shape optimization showing robustness and computational efficiency in comparison with FEM solutions obtained with a commercial code, despite the fact that cg-FEM has been fully implemented in MATLAB.This work has been developed within the framework of research project DPI2010-20542 of the Ministerio de Economia y Competitividad (Spain). The financial support of the FPU program (AP2008-01086), the funding from Universitat Politecnica de Valencia, and Generalitat Valenciana (PROMETEO/2012/023) are also acknowledged. The authors also thank the support of the Framework Programme 7 Initial Training Network Funding under Grant no. 289361 "Integrating Numerical Simulation and Geometric Design Technology."Nadal, E.; Ródenas, J.; Albelda Vitoria, J.; Tur Valiente, M.; Tarancón Caro, JE.; Fuenmayor Fernández, FJ. (2013). Efficient finite element methodology based on cartesian grids: application to structural shape optimization. Abstract and Applied Analysis. 2013:1-19. https://doi.org/10.1155/2013/953786S1192013Moés, N., Dolbow, J., & Belytschko, T. (1999). A finite element method for crack growth without remeshing. International Journal for Numerical Methods in Engineering, 46(1), 131-150. doi:10.1002/(sici)1097-0207(19990910)46:13.0.co;2-jSukumar, N., & Prévost, J.-H. (2003). Modeling quasi-static crack growth with the extended finite element method Part I: Computer implementation. 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Equilibrated patch recovery error estimates: simple and accurate upper bounds of the error. International Journal for Numerical Methods in Engineering, 69(10), 2075-2098. doi:10.1002/nme.1837Ródenas, J. J., González-Estrada, O. A., Díez, P., & Fuenmayor, F. J. (2010). Accurate recovery-based upper error bounds for the extended finite element framework. Computer Methods in Applied Mechanics and Engineering, 199(37-40), 2607-2621. doi:10.1016/j.cma.2010.04.010Ainsworth, M., & Oden, J. T. (2000). A Posteriori Error Estimation in Finite Element Analysis. doi:10.1002/9781118032824Xiao, Q. Z., & Karihaloo, B. L. (2006). Improving the accuracy of XFEM crack tip fields using higher order quadrature and statically admissible stress recovery. International Journal for Numerical Methods in Engineering, 66(9), 1378-1410. doi:10.1002/nme.1601Bordas, S., & Duflot, M. (2007). Derivative recovery and a posteriori error estimate for extended finite elements. 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Critical properties of Ising model on Sierpinski fractals. A finite size scaling analysis approach

The present paper focuses on the order-disorder transition of an Ising model on a self-similar lattice. We present a detailed numerical study, based on the Monte Carlo method in conjunction with the finite size scaling method, of the critical properties of the Ising model on some two dimensional deterministic fractal lattices with different Hausdorff dimensions. Those with finite ramification order do not display ordered phases at any finite temperature, whereas the lattices with infinite connectivity show genuine critical behavior. In particular we considered two Sierpinski carpets constructed using different generators and characterized by Hausdorff dimensions d_H=log 8/log 3 = 1.8927.. and d_H=log 12/log 4 = 1.7924.., respectively. The data show in a clear way the existence of an order-disorder transition at finite temperature in both Sierpinski carpets. By performing several Monte Carlo simulations at different temperatures and on lattices of increasing size in conjunction with a finite size scaling analysis, we were able to determine numerically the critical exponents in each case and to provide an estimate of their errors. Finally we considered the hyperscaling relation and found indications that it holds, if one assumes that the relevant dimension in this case is the Hausdorff dimension of the lattice.Comment: 21 pages, 7 figures; a new section has been added with results for a second fractal; there are other minor change

Domain integral formulation for 3-D curved and non-planar cracks with the extended finite element method

The computation of stress intensity factors (SIFS) in curved and non-planar cracks using domain integrals introduces some difficulties related to the use of curvilinear gradients. Several approaches exist in the literature that consider curvilinear corrections within a finite element framework, but these depend on each particular crack configuration and they are not general. In this work, we introduce the curvilinear gradient correction within the extended finite element method framework (XFEM), based only on the level set information used for the crack description and the local coordinate system definition. Our formulation depends only on the level set coordinates and, therefore, an explicit analytical description of the crack is not needed. It is shown that this curvilinear correction improves the results and enables the study of generic cracks. In addition, we have introduced a simple error indicator for improving the SIF computed via the interaction integral, thanks to the better behavior of the J-integral as it does not need auxiliary extraction fields.This work has been carried out within the framework of the research projects DPI2007-66995-C03-02 and DPI2010-20990 financed by the Ministerio de Economia y Competitividad. The support of the Generalitat Valenciana, Programme PROMETEO 2012/023 is also acknowledged.González Albuixech, VF.; Giner Maravilla, E.; Tarancón Caro, JE.; Fuenmayor Fernández, FJ.; Gravouil, A. (2013). Domain integral formulation for 3-D curved and non-planar cracks with the extended finite element method. Computer Methods in Applied Mechanics and Engineering. 264:129-144. https://doi.org/10.1016/j.cma.2013.05.016S12914426

Calculation of the critical energy release rate Gc of the cement line in cortical bone combining experimental tests and finite element models

[EN] In this work, a procedure is proposed to estimate the critical energy release rate Gc of the so-called cement line in cortical bone tissue. Due to the difficulty of direct experimental estimations, relevant elastic and toughness material properties at bone microscale have been inferred by correlating experimental tests and finite element simulations. In particular, three-point bending tests of ovine cortical bone samples have been performed and modeled by finite elements. The initiation and growth of microcracks in the tested samples are simulated through finite elements using a damage model based on a maximum principal strain criterion, showing a good correlation with the experimental results. It is observed that microcracks evolve mainly along the cement lines and through the interstitial material but without crossing osteons. The numerical model allows the calculation of the cement line critical energy release rate Gc by approximating its definition by finite differences. This way, it is possible to estimate this property poorly documented in the literature.The authors wish to thank the Ministerio de Economia y Competitividad for the support received in the framework of the project DPI2013-46641-R and to the Generalitat Valenciana, Programme PROMETEO 2016/007. The authors also thank Dr. Jose Luis Peris, from Instituto de Biomecanica de Valencia (IBV) and Carlos Tudela Desantes for their collaboration within the context of the project.Giner Maravilla, E.; Belda, R.; Arango-Villegas, C.; Vercher Martínez, A.; Tarancón Caro, JE.; Fuenmayor Fernández, FJ. (2017). Calculation of the critical energy release rate Gc of the cement line in cortical bone combining experimental tests and finite element models. Engineering Fracture Mechanics. 184:168-182. https://doi.org/10.1016/j.engfracmech.2017.08.026S16818218

Homogenized stiffness matrices for mineralized collagen fibrils and lamellar bone using unit cell finite element models

Mineralized collagen fibrils have been usually analyzed like a two phase composite material where crystals are considered as platelets that constitute the reinforcement phase. Different models have been used to describe the elastic behavior of the material. In this work, it is shown that, when Halpin-Tsai equations are applied to estimate elastic constants from typical constituent properties, not all crystal dimensions yield a model that satisfy thermodynamic restrictions. We provide the ranges of platelet dimensions that lead to positive definite stiffness matrices. On the other hand, a finite element model of a mineralized collagen fibril unit cell under periodic boundary conditions is analyzed. By applying six canonical load cases, homogenized stiffness matrices are numerically calculated. Results show a monoclinic behavior of the mineralized collagen fibril. In addition, a 5-layer lamellar structure is also considered where crystals rotate in adjacent layers of a lamella. The stiffness matrix of each layer is calculated applying Lekhnitskii transformations and a new finite lement model under periodic boundary conditions is analyzed to calculate the homogenized 3D anisotropic stiffness matrix of a unit cell of lamellar bone. Results are compared with the rule-of-mixtures showing in general good agreement.The authors acknowledge the Ministerio de Economia y Competitividad the financial support given through the project DPI2010-20990 and the Generalitat Valenciana through the Programme Prometeo 2012/023. The authors thank Ms. Carla Gonzalez Carrillo by her help in the development of some of the numerical models.Vercher Martínez, A.; Giner Maravilla, E.; Arango Villegas, C.; Tarancón Caro, JE.; Fuenmayor Fernández, FJ. (2014). Homogenized stiffness matrices for mineralized collagen fibrils and lamellar bone using unit cell finite element models. 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Targeted-pig trial on safety and immunogenicity of serum-derived extracellular vesicles enriched fractions obtained from Porcine Respiratory and Reproductive virus infections

The Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is the etiological agent of one of the most important swine diseases with a significant economic burden worldwide. Unfortunately, available vaccines are partially effective highlighting the need of novel approaches. Previously, antigenic viral proteins were described in serum-derived extracellular vesicles (EVs) from pigs previously infected with PRRSV. Here, a targeted-pig trial was designed to determine the safety and immunogenicity of such extracellular vesicles enriched fractions. Our results showed that immunizations with EV-enriched fractions from convalescence animals in combination with montanide is safe and free of virus as immunizations with up-to two milligrams of EV-enriched fractions did not induce clinical symptoms, adverse effects and detectable viral replication. In addition, this vaccine formulation was able to elicit specific humoral IgG immune response in vaccinated animals, albeit variably. Noticeably, sera from vaccinated animals was diagnosed negative when tested for PRRSV using a commercial ELISA test; thus, indicating that this new approach differentiates vaccinated from infected animals. Lastly, after priming animals with EV-enriched fractions from sera of convalescence animals and boosting them with synthetic viral peptides identified by mass spectrometry, a distinctive high and specific IFN-γ response was elicited. Altogether, our data strongly suggest the use of serum EV-enriched fractions as a novel vaccine strategy against PRRSV